The immune system is the power of the body to resist invasion by pathogenic organisms, and to overcome such invasion and its ensuing infection, once it has taken place. The complement system is important in the immune response. Complement is a physiological process which involves many plasma proteins that react in a cascading (sequential) effect to mediate a number of desirable biologically significant phenomena. Such phenomena include modulation of the immune response, facilitation of the transport of immune complexes, production of anaphylatoxins which cause release of histamine, chemotaxis which is the migration of cells towards the area of complement activity, phagocytosis, and lysis of cells.
The activation of the complement cascade can also cause undesirable phenomena, such as inflammation, damage of normal tissue and disease states such as the autoimmune diseases. Autoimmune diseases are associated with the immune complexes formed against indigenous tissue which are associated with the biologically active complement fragments generated by the classical portion of the complement cascade. Such diseases include but are not limited to: Hashimoto's thyroiditis, systemic lupus erythematosis, Goodpasture's syndrome, Graves' disease, myasthenia gravis, insulin resistance, autoimmune hemolyic anemia, autoimmune thrombocytopenic prupura, and rheumatoid arthritis.
It is known that the first phase of complement activation begins with C1. C1 is made up of three distinct proteins: a recognition subunit, C1q, and the serine proteinase subcomponents, C1r and C1s which are bound together in a calcium-dependent tetrameric complex, C1r.sub.2 s.sub.2. An intact C1 complex is necessary for physiological activation of C1 to result. Activation occurs when the intact C1 complex binds to immunoglobulin complexed with antigen. This binding activates C1s which would then react with the next plasma protein, C4, to start the cascading effect rolling.
In terms of the regulation of the complement system, most studies have focused on the binding properties of the C1 serine proteinase subcomponents, C1r and C1s, for a serum glycoprotein, C1 Inhibitor. Another inhibitor that has been identified but whose role in regulating C1 function in plasma is not clear is the C1q inhibitor (C1qINH).
It is important to identify and isolate inhibitors of the complement system because by isolating an inhibitor one may be able to control the effects of diseases such as those stated above. The inhibitors may provide a basis for pharmacologic intervention, either by allowing manipulation of the level of an inhibitor, or by providing a model for the chemical synthesis of a new inhibitor.
It is therefore an object of the present invention to provide a method for the isolation of an inhibitor of C1 which is functionally and antigenically distinct from known inhibitors of C1.
It is more specifically an object of the present invention to characterize the properties of an inhibitor of C1, factor J.